Effects of Cabozantinib on Human G292 Osteosarcoma Cells

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Longjie Chen Dinh Nguyen Ryan Kaminsky Jennifer Helfer Rosemary Dziak, Ph.D.


Cabozantinib (CBZ) N-(4-((6,7-dimethoxyquinolin-4-yl) oxy) phenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide) (XL184), an inhibitor of MET and vascular endothelial growth factor receptor (VEGFR-2), is an agent approved for the treatment of several types of carcinoma such as medullary thyroid and renal. Recent studies are encouraging for the effectiveness of CBZ in the treatment of osteosarcoma. Because of the complex nature of the microenvironment of osteosarcoma cell sites, in order to better understand the direct effects of CBZ on osteosarcoma cells, in vitro studies were conducted with the human osteosarcoma cell line, G292. Experiments were focused on the effects of CBZ on cell metabolic activity, differentiation, and apoptosis as well as the modulation of responses to growth factors such as platelet-derived growth factor (PDGF) and insulin like growth factor (IGF-I). The results indicate that CBZ can increase the activity of caspase 3/7 as an indicator of apoptosis as well as decrease cellular activity, measured by MTT assay and differentiation assessed by alkaline phosphatase activity. The drug partially downregulated the effects of PDGF on MTT activity and had significant inhibitory effects on the G292 cells response to IGF-I and production of VEGF.

This study presents original information on responses of G292 human osteosarcoma cells to the chemotherapy agent, CBZ, and provides in vitro data consistent with the potential therapeutic effects of this agent for osteosarcoma.

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How to Cite
CHEN, Longjie et al. Effects of Cabozantinib on Human G292 Osteosarcoma Cells. Medical Research Archives, [S.l.], v. 9, n. 9, sep. 2021. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2554>. Date accessed: 24 feb. 2024. doi: https://doi.org/10.18103/mra.v9i9.2554.
Research Articles


1. Nix NM, Braun K. Cabozantinib for the treatment of metastatic medullary thyroid carcinoma. J Adv Pract Oncol. 2014;5: 47–50
2. Karras S, Pontikides N, Krassas GE. Pharmacokinetic evaluation of cabozantinib for the treatment of thyroid cancer. Expert opinion on drug metabolism & toxicology. 2013; 9:507-515
3. Trojan J. Cabozantinib for the treatment of advanced hepatocellular carcinoma: current data and future perspectives. Drugs. 2020;1-8
4. Singh H, Brave M, Beaver JA, Cheng J, Tang S, Zahalka E, et al.
U.S. food and drug administration approval: cabozantinib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2017; 23:330–335
5. Smith M, De Bono J, Sternberg C, et al. Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol. 2016: Sep 1;34
6. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31: 412–419

7. Smith MR, Sweeney CJ, Corn PG, et al. Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol. 2014;32(30):3391–3399
8. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17: 917–927
9. Stern PH, Alvares K. Antitumor Agent Cabozantinib Decreases RANKL Expression in Osteoblastic Cells and Inhibits Osteoclastogenesis and PTHrP‐Stimulated Bone Resorption. Journal of cellular biochemistry. 2014; 115(11):2033-2038
10. Fioramonti M, Santini D, Iuliani M, Ribelli G, Manca P, Papapietro N, Spiezia F, Vincenzi B. Denaro V, Russo A et al. Cabozantinib targets bone microenvironment modulating human osteoclast and osteoblast functions. Oncotarget. 2017; 8: 20113–20121
11. Pan T, Martinez M, Hubka KM, Song JH, Lin SC, Yu G, Lee YC, Gallick GE, Tu SM, Harrington DA, Farach-Carson MC, Lin SH, Satcher RL. Cabozantinib Reverses Renal Cell Carcinoma-mediated Osteoblast Inhibition in Three-dimensional Coculture In Vitro and Reduces Bone Osteolysis In Vivo. Mol Cancer Ther. 2020; Jun;19(6):1266-1278
12. Italiano A, Mir O, Mathoulin-Pelissier S, Penel N, Piperno-Neumann S, Bompas E, Chev C, Duaud F, Entz-Werle N, Saada E et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020; 21: 446- 455
13. Fioramonti M, Fausti V, Pantano F. Iuliani M, Ribelli G, Lotti F, Pignochino Y. et al. Cabozantinib affects osteosarcoma growth through a direct effect on tumor cells and modifications in bone microenvironment. Scientific reports. 2018; 8(1): 1-11
14. Allori AC, Sailon AM, Warren SM. Biological basis of bone formation, remodeling, and repair - Part I: Biochemical signaling molecules. Tissue Eng Part B Rev. 2008;14: 275-283
15. Sheng MH, Lau KH, Baylink DJ. Role of osteocyte-derived insulin-like growth factor I in developmental growth, modeling, remodeling, and regeneration of the bone. J Bone Metab. 2014; 21:41–54
16. Fernandes G, Barone AW, Dziak R. The effect of ascorbic acid on bone cancer cells in vitro. Cogent Biology. 2017; 3(1):1288335
17. Raymond AK, Jaffe N. Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. Pediatric and Adolescent Osteosarcoma. 2009:63-84
18. Misaghi A, Goldin A, Awad M, Kulidjian AA. Osteosarcoma: a comprehensive review. SICOT J. 2018; 4:12

19. Tian Z, Niu X, Yao W. Receptor tyrosine kinases in osteosarcoma treatment: which is the key target?. Frontiers in Oncology. 2020 Aug 28; 10:1642
20. Lauvrak SU, Munthe E, Kresse SH, Stratford EW, Namløs HM, Meza-Zepeda LA, Myklebost O. Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes. British journal of cancer. 2013; 109(8): 2228-2236
21. Toosi S, Behravan J. Osteogenesis and bone remodeling: A focus on growth factors and bioactive peptides. Biofactors. 2020; 46(3):326-340
22. Colciago A, Celotti F, Casati L, et al. In Vitro Effects of PDGF Isoforms (AA, BB, AB and CC) on Migration and Proliferation of SaOS-2 Osteoblasts and on Migration of Human Osteoblasts. Int J Biomed Sci. 2009;5(4):380-389
23. Kappel CC, Velez-Yanguas MC, Hirschfeld S, Helman LJ. Human osteosarcoma cell lines are dependent on insulin-like growth factor I for in vitro growth. Cancer Research. 1994; 54(10): 2803-2807
24. Assi T, Watson S, Samra B, Rassy E, Le Cesne A, Italiano A, Mir O. Targeting the VEGF Pathway in Osteosarcoma. Cells. 2021; 10:1240-1255
25. Liu Y, Zhang F, Zhang Z, Wang D, Cui B, Zeng F, Huang L, Zhang Q, Sun Q. High expression levels of Cyr61 and VEGF are associated with poor prognosis in osteosarcoma. Pathology-Research and Practice. 2017; 213(8): 895-899
26. Fagioli F, Tirtei, E. Cabozantinib: a new perspective for advanced bone sarcoma. The Lancet Oncology. 2020; 21(3): 331-332